Approximately 6000 VA admissions for stroke occur each year. Current rates of functional recovery from movement-related deficits after stroke are largely unsatisfying. Economic burdens continue to place limits on the length of rehabilitation, emphasizing a need for new strategies that increase the efficacy and efficiency of rehabilitation programs. Neuromodulatory strategies involving cortical stimulation have been examined as adjunctive therapies to enhance rehabilitation outcomes after stroke. It has been proposed that targeting other neural structures may offer new avenues to enhance the effects of rehabilitation. The broad objective of the proposed research is to strengthen corticospinal transmission to hemiparetic intrinsic hand muscles in veterans with stroke by targeting corticomotoneuronal synapses in the spinal cord based on principles of spike timing-dependent plasticity. There are two major goals for satisfying this objective: 1) examine functional and structural neurophysiological mechanisms underlying the response to this neuromodulatory strategy, and 2) explore how corticomotoneuronal synaptic plasticity after stroke can enhance voluntary motor output and drive progression during motor retraining. Presynaptic and postsynaptic action potentials will be timed to arrive at the corticomotoneuronal synapse in a particular sequence and within a specific temporal window based on conduction times calculated from individual response latencies. In Aim 1, repeated pre- and postsynaptic action potentials will be delivered and various neurophysiological responses will be measured to evaluate changes in corticospinal transmission. In Aim 2, the triple stimulation technique will be used to measure failures in central conduction, and diffusion spectrum imaging fractional anisotropy will be used to estimate corticospinal spinal tract integrity. These functional and structural characteristics will be used to evaluate the response to neuromodulation targeting synapses in the spinal cord. Aim 3 experiments will test how the change in corticospinal transmission alters the control of voluntary motor output during visuomotor task performance. Building on the first three aims investigating mechanisms of plasticity, Aim 4 will pilot a mechanism-driven intervention to enhance progression during motor retraining. The research team is comprised of experts in the areas of neurophysiology, neural engineering, neuroimaging, and stroke neurorehabilitation and, therefore, is well positioned to satisfy the proposed project goals. This Career Development Award will also help establish Dr. Urbin as an independent investigator within the VA RR&D service. Dr. Urbin is committed to pursuing a clinical research career with the objective of developing a line of inquiry that promotes restored functional independence for veterans living with disability. The training experiences that will take place as part of this award will allow Dr. Urbin to acquire new skills in neuroimaging and advanced neurostimulation techniques. Additional activities in the career development plan overseen by the mentorship team will provide the necessary training for him to achieve independent status. Overall, this award will help Dr. Urbin along the path to developing a recognized research program within the VA scientific community.